PROJECT SUMMARY/ABSTRACT Prostate cancer is the most common cancer in men in the United States. The first line of treatment for men with aggressive prostate cancer is hormone therapy or androgen ablation therapy. Although initial responses are observed, unfortunately, the disease commonly recurs in its aggressive hormone therapy-resistant form also known as castration resistant prostate cancer (CRPC). Current therapies for hormone therapy resistant prostate cancer or CRPC prolong the patients? lifespan by only a few months. Thus, there is an urgent need to identify the molecular mechanisms underlying the development of CRPC and define new strategies to overcome aggressive prostate cancer. Trop2 is a cell surface protein that is found altered in multiple types of human cancers. Our recent studies demonstrate that Trop2 is a novel promising therapeutic target for aggressive prostate cancer due to its high expression in advanced prostate cancer and its oncogenic role in the disease. The goals of the proposed research are to: 1) Investigate the molecular mechanisms through which Trop2 contributes to the development of the aggressive disease. 2) Develop new inhibitors to block Trop2 function as a novel therapeutic strategy for advanced prostate cancer. The completion of the proposed project will lead to defining new therapeutic targets and uncover novel therapies for aggressive prostate cancer. The proposed project will develop new therapeutic strategies to inhibit Trop2 receptor in aggressive prostate cancer in pre-clinical settings creating an important translational link between the proposed research and the treatment of patients with aggressive prostate cancer in the near future. Due to the high expression of Trop2 in many epithelial cancers, we believe that our findings will be applicable to a broad range of cancers.